ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.8G>A (p.Arg3Gln) (rs375507981)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200703 SCV000254620 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3 of the PMS2 protein (p.Arg3Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs375507981, ExAC 0.02%). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216462). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000570033 SCV000663550 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-22 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001199853 SCV001370585 uncertain significance not specified 2020-05-29 criteria provided, single submitter clinical testing Variant summary: PMS2 c.8G>A (p.Arg3Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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